Baseline Measurements of Cellular Respiration Affect the Response to Thiamine Treatment in Post-arrest Patients

Introduction: Lactic acidosis and impaired oxygen extraction due to mitochondrial dysfunction are common post-arrest. Thiamine, a cofactor for pyruvate dehydrogenase, is necessary for aerobic metabolism. In two randomized controlled trials (RCTs) testing the effect of thiamine vs. placebo in out-of-hospital and in-hospital post-arrest patients (NCT03450707 and NCT02974257), no relationship was found between thiamine treatment and the primary outcome of change in lactate over 24 hours. Cellular oxygen consumption rates (OCRs) were measured in a subset of patients at baseline. Maximal and spare OCRs measure the capacity of mitochondria to increase cellular respiration from their basal state when stimulated, and may identify patients likely to benefit from thiamine. We conducted a post-hoc analysis of the two RCTs to evaluate the primary outcome in subgroups defined by baseline OCRs. Hypothesis: Patients with higher maximal and spare OCRs at baseline are more likely to benefit from thiamine treatment, as indicated by lower lactate levels. Methods: Basal, maximal and spare OCRs, collected at enrollment, were measured in peripheral blood mononuclear cells using an XFe96 Extracellular Flux Analyzer and XF Cell Mito Stress Test Kit (Seahorse Bioscience). Lactates (at 6, 12, and 24 hours) were log-transformed and analyzed using a linear mixed model controlling for baseline lactate. In patients who expired <24 hours, lactate was imputed using the last available value with a 20% increase. Subgroups were defined by baseline OCR values above or below the median. The primary outcome was lactate at 24 hours, presented as a geometric mean difference (GMD). Results: A total of 74 patients had baseline OCR measurements. There was no statistically significant difference in lactate at 24 hours between placebo and thiamine in all patients (p=0.179) or in the low OCR (below median) groups. In patients with baseline maximum or spare OCRs above the median, lactate levels were significantly lower in those receiving thiamine (24 hour GMDs of 0.61 (95% CI: 0.45-0.82; p=0.001), and 0.53 (95% CI: 0.38-0.74; p<0.001), respectively; Figure 1). Conclusion: In a post-hoc analysis of two RCTs, thiamine significantly improved the primary outcome in the subgroup of patients with higher spare and maximal oxygen consumption rates at baseline. Baseline OCRs could potentially identify post-arrest patients likely to benefit from thiamine.